CN102428079B - Imidazolidine-2,4-dione derivatives and use thereof as a medicament - Google Patents

Imidazolidine-2,4-dione derivatives and use thereof as a medicament Download PDF

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CN102428079B
CN102428079B CN201080021640.0A CN201080021640A CN102428079B CN 102428079 B CN102428079 B CN 102428079B CN 201080021640 A CN201080021640 A CN 201080021640A CN 102428079 B CN102428079 B CN 102428079B
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D·比戈
S·欧文
C·兰库
G·普雷沃
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Abstract

The subject matter of the present application is novel imidazolidine-2,4-dione derivatives of general formula (I) shown in the description, in which R1, R2, R3 and X are variables. These products have an anti-proliferative activity. They are particularly advantageous for treating pathological conditions and diseases associated with abnormal cell proliferation, such as cancers. The invention also relates to pharmaceutical compositions containing said products and to the use thereof for preparing a medicament.

Description

Imidazolidine-2,4-dione derivative and as the purposes of medicine
Invention field
The application's theme is novel imidazole alkane-2,4-derovatives.These products have antiproliferative activity.They are used in particular for treatment and pathologic state and the disease of for example related to cancer of abnormal cell proliferation.The invention still further relates to the pharmaceutical composition that contains described product and they purposes for the preparation of medicine.
The state of the art
Current, although there are many molecules in pharmaceutical market, cancer still forms one of major causes of death.
Therefore, be necessary to identify more effectively recruit, they especially provide better antitumor reaction by tumour cell colony being had to good inhibition activity.
This quasi-molecule thereby be used in particular for the treatment pathologic state relevant with abnormal cell proliferation.Therefore, they can be used for treating tumour or cancer, for example esophagus, stomach, intestines, rectum, oral cavity, pharynx, larynx, lung, colon, breast, uterine cervix, body of uterus inner membrance, ovary, prostate gland, testis, bladder, kidney, liver, pancreas, bone, reticular tissue, skin are as the tumour of melanoma, eye, brain and central nervous system or cancer, and thyroid carcinoma, leukemia, Hodgkin's disease, non-Hodgkin lymphoma, multiple myeloma and other cancer.
Especially interestingly, find the therapy of tumour, breast and the prostatic cancer of hormonal dependent cancer, expression androgen receptor.
The use of anti-androgens in prostate cancer is to enter the characteristic of competing with the natural agonist of androgen receptor based on them.But it seems that the effect of these anti-androgenses be restricted along with the time, final, treatment is failed patient.Several hypothesis about this failure have been formed, show that agonist activity substitutes antagonistic activity (Veldscholte J, Berrevoets CA, the Brinkmann AO of these molecules, Grootegoed JA, Mulder E.Biochemistry on March 3rd, 1992; 31 (8): 2393-9).For example, Nilutamide can stimulate the growth of people prostatitis cancer cells in culture.Except these experiment indications, clinical data is also supported this deleterious effect (Akimoto S. of anti-androgens; Antiandrogen withdrawal syndrome Nippon Rinsho.1998 August; 56 (8): 2135-9.Paul R, Breul J.Antiandrogen withdrawal syndrome associated with prostate cancer therapies:incidence and clinical significance Drug Saf.2000 November; 23 (5): 381-90).
In this case, applicant has identified tumor of prostate has been shown to the compound of antiproliferative activity, and surprisingly, this compound shows as in Nilutamide under the concentration of agonist and do not demonstrate agonist activity.The ability that the performance of new compound aspect propagation disappeared by the androgen receptor of their induced protein forms than the difference of Nilutamide is supported.Nilutamide on this type of receptor level without any impact.
This type of recruit's character must allow to control better prostate cancer, avoids the failure of current anti-androgens.
Such as, and compound of the present invention also can be used for the treatment pathology relevant with the existence of androgen receptor, benign prostate hyperplasia, prostatomegaly (prostamegaly), acne, androgenetic alopecia, hirsutism etc.
Summary of the invention
Therefore, the compound or pharmaceutically acceptable salt thereof that themes as general formula (I) of the present invention,
Figure BDA0000109325180000021
Wherein:
R 1represent cyano group, nitro, amino ,-NHCOOR 4or-NHCOR 4group;
R 2represent halo, alkyl, haloalkyl or alkoxy base;
R 3represent alkyl group or hydrogen atom; Or two R 3together with the carbon atom that group connects with them, form the cycloalkyl that contains 3-4 member;
X represents
● have the straight or branched alkylidene chain of 3 to 7 carbon atoms, this chain can comprise one or more being selected from-O-,-N (R 5)-,-S-,-SO-or-SO 2-other identical or different member; Or
● or
Figure BDA0000109325180000031
group,
Wherein n1 and p1 are two integers, its n1+p1 and be to be selected from 2,3,4 or 5 integer;
R 6and R 7form together covalent linkage, or R 6and R 7together with the carbon atom connecting with them, form
Figure BDA0000109325180000032
ring or the cycloalkyl that contains 3 to 6 members;
R 4represent alkyl, aryl or heteroaryl groups;
R 5represent hydrogen, alkyl or aromatic alkyl group.
Preferably, X represents to have the straight or branched alkylidene chain of 3 to 7 carbon atoms, and this chain can comprise one or more being selected from-O-,-N (R 5)-,-S-,-SO-or-SO 2-other identical or different member.
More preferably, X represents alkylidene chain, and this chain can comprise single being selected from-O-,-N (R 5)-,-S-,-SO-or-SO 2-member.
According to modification, X represents
Figure BDA0000109325180000033
group,
Wherein n1 and p1 are two integers, its n1+p1 and be to be selected from 2,3,4 or 5 integer;
R 6and R 7form together covalent linkage, or R 6and R 7together with the carbon atom connecting with them, form
Figure BDA0000109325180000034
ring or the cycloalkyl that contains 3 to 6 members;
Preferably, n1 and p1 equate.
Preferably, n1+p1 and equal 2.Preferably, n1+p1 and equal 3.Preferably, n1+p1 and equal 4.Preferably, n1+p1 and equal 5.
According to another modification, represent-(CH of X 2) n 2-X '-(CH 2) p 2group, and X ' expression-O-,-N (R 5)-or-S-,-SO-,-SO 2-,-CH 2-or
Figure BDA0000109325180000035
group, and n2 and p2 be integer, wherein n2+p2's and work as X ' expression-O-,-N (R 5)-,-S-,-SO-,-SO 2during-group, be to be selected from 3,4,5,6 and 7 integer, or work as X ' expression-CH 2-or
Figure BDA0000109325180000041
during group, be to be selected from 2,3,4 and 5 integer.
Preferably, X ' represents
Figure BDA0000109325180000042
group.
Preferably, X ' expression-O-,-N (R 5)-or-(CH 2)-group.
Preferably, n2 and p2 equate.
Preferably, n2+p2 and equal 2.Preferably, n2+p2 and equal 3.Preferably, n2+p2 and equal 4.Preferably, n2+p2 and equal 5.Preferably, n2+p2 and equal 6.Preferably, n2+p2 and equal 7.
Preferably, R 3represent alkyl group or two R 3together with the carbon atom that group connects with them, form the cycloalkyl that contains 3-4 member.
Preferably, R 4represent alkyl group.
Preferably, R 5represent alkyl group.
Preferably, X represents to have the straight-chain alkyl-sub-chain of 3 to 7 carbon atoms.
Preferably, R 1in contraposition.
Preferably, R 2in a position.
Preferably, R 2represent halogenated alkyl group.
Preferably, R 6and R 7form together covalent linkage.
Preferably, R 6and R 7together with the carbon atom connecting with them, form
Figure BDA0000109325180000043
ring.
Preferably, R 6and R 7together with the carbon atom connecting with them, form the cycloalkyl that contains 3 to 6 members.
According to another modification, R 3represent alkyl group or hydrogen; And be preferably alkyl group.
Preferably, R 4represent alkyl group, and R 5represent alkyl group.
Preferably,
R 1represent cyano group, nitro, amino ,-NHCOOR 4or-NHCOR 4group;
R 2represent halo, alkyl, haloalkyl, alkoxy base;
R 3represent alkyl group;
X represents to have the straight or branched alkylidene chain of 3 to 7 carbon atoms, this chain can comprise other-O-or-N (R 5)-member;
R 4represent alkyl group;
And R 5represent alkyl group.
Even more preferably, R 1represent cyano group, nitro or-NHCOOR 4group.
Equally most preferably, X represents to have the alkylidene chain of 4-7 carbon atom, and this chain can comprise other-O-member.
Preferably, alkyl group represents methyl group.
Formula (I) compound is preferably selected from:
1,1 '-butane-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-hexane-1,6-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-heptane-1,7-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
1,1 '-(3-methylpentane-1,5-bis-bases) 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }
1,1 '-(oxygen base two ethane-2,1-bis-bases) 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-pentane-1,5-bis-bases two 3-[4-amino-3-(trifluoromethyl) phenyl] and-5,5-methylimidazole alkane-2,4-diketone }
N, N '-(pentane-1,5-bis-bases two { (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases) [2-(trifluoromethyl)-4,1-phenylene] }) diethylamide
1,1 '-pentane-1,5-bis-bases two [5,5-dimethyl-3-(3-methyl-4-nitrophenyl)-imidazolidine-2,4-dione]
1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-2-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-pentane-1,5-bis-bases two [3-(3-chloro-4 nitrophenyl)-5,5-dimethyl-imidazolidine-2,4-dione]
1,1 '-pentane-1,5-bis-bases two [3-(3-methoxyl group-4-nitrophenyl)-5,5-dimethyl-imidazolidine-2,4-dione]
{ pentane-1,5-bis-bases two [(4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases) (2-methyl-4,1-phenylene)] } diamino acid dimethyl ester
4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-methyl benzonitriles)
4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-benzyl chloride nitriles)
1,1 '-propane-1,3-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl]-2,4-dioxo alkyl imidazole-1-yl } and-N-(2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-2,4-dioxo alkyl imidazole-1-yl } ethyl)-N-methyl ethyl-amine
1,1 '-(2Z)-but-2-ene-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }
4,4 '-[pentane-1,5-bis-bases two (5,7-dioxo-4,6-diaza spiro [2.4] heptane-4,6-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
4,4 '-[(2Z)-but-2-ene-Isosorbide-5-Nitrae-bis-base two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
4,4 '-{ (2R, 3S)-oxyethane-2,3-bis-bases two [methane two bases (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] } two [2-(trifluoromethyl) benzonitriles]
4,4 '-{ (1R, 2R)-cyclopropane-1,2-bis-bases two [methane two bases (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] } two [2-(trifluoromethyl) benzonitriles]
Or the pharmaceutically useful salt of this compound;
Especially, formula (I) compound is selected from:
1,1 '-butane-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-hexane-1,6-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-heptane-1,7-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
1,1 '-(3-methylpentane-1,5-bis-bases) 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }
1,1 '-(oxygen base two ethane-2,1-bis-bases) 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-pentane-1,5-bis-bases two 3-[4-amino-3-(trifluoromethyl) phenyl] and-5,5-methylimidazole alkane-2,4-diketone }
N, N '-(pentane-1,5-bis-bases two { (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases) [2-(trifluoromethyl)-4,1-phenylene] }) diethylamide
1,1 '-pentane-1,5-bis-bases two [5,5-dimethyl-3-(3-methyl-4-nitrophenyl)-imidazolidine-2,4-dione]
1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-2-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-pentane-1,5-bis-bases two [3-(3-chloro-4 nitrophenyl)-5,5-dimethyl-imidazolidine-2,4-dione]
1,1 '-pentane-1,5-bis-bases two [3-(3-methoxyl group-4-nitrophenyl)-5,5-dimethyl-imidazolidine-2,4-dione]
{ pentane-1,5-bis-bases two [(4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases) (2-methyl-4,1-phenylene)] } diamino acid dimethyl ester
4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-methyl benzonitriles)
4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-benzyl chloride nitriles)
1,1 '-propane-1,3-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl]-2,4-dioxo alkyl imidazole-1-yl } and-N-(2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-2,4-dioxo alkyl imidazole-1-yl } ethyl)-N-methyl ethyl-amine
1,1 '-(2Z)-but-2-ene-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }
4,4 '-[pentane-1,5-bis-bases two (5,7-dioxo-4,6-diaza spiro [2.4] heptane-4,6-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
4,4 '-[(2Z)-but-2-ene-Isosorbide-5-Nitrae-bis-base two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
4,4 '-{ (2R, 3S)-oxyethane-2,3-bis-bases two [methane two bases (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] } two [2-(trifluoromethyl) benzonitriles]
4,4 '-{ (1R, 2R)-cyclopropane-1,2-bis-bases two [methane two bases (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] } two [2-(trifluoromethyl) benzonitriles]
Or the pharmaceutically useful salt of this compound;
Preferably, the compound of general formula (I) is selected from:
1,1 '-butane-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-(oxygen base two ethane-2,1-bis-bases) 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-methyl benzonitriles)
1,1 '-(2Z)-but-2-ene-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }
Or its pharmaceutically useful salt.
More particularly, formula (I) compound is selected from:
1,1 '-butane-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-(oxygen base two ethane-2,1-bis-bases) 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-methyl benzonitriles)
1,1 '-(2Z)-but-2-ene-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }
Or the pharmaceutically useful salt of this compound.
Preferably, the compound of formula (I) is 1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione } or 1,1 '-(2Z)-but-2-ene-1,4-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }.
Quite especially, formula (I) compound is 1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }.
Theme of the present invention is also that described method comprised by the stage forming below for the preparation of the method for formula (I) compound as defined above
(i) by the aryl glycolylurea of the general formula of two equivalents (II),
Figure BDA0000109325180000101
Wherein R 2and R 3as defined above, and R 1nitro or cyano group,
Under the existence of highly basic with general formula Gp 1-X-Gp 2derivative condensation, Gp 1and Gp 2leavings group,
And X is as defined above,
To form the compound of general formula (I)
Figure BDA0000109325180000102
Wherein R 2, R 3with X as defined above, and R 1nitro or cyano group.
Preferably, condensation is by reaction mixture being heated to 20 ℃ to 100 ℃, preferably the temperature of 45 ℃ to 65 ℃ is carried out.
Preferably, reaction is carried out in proton-inert polar solvent.
Preferably, the method also comprised with the next stage:
(ii) reduction nitryl group is so that acquisition formula (III) compound,
Figure BDA0000109325180000103
Preferably, the method also comprised by the stage forming below:
(iii) formula (III) compound and the general formula R that will in the stage (ii), obtain 4the acyl chloride reaction of-COCl, wherein
R 4as defined above, so that acquisition formula (IV) compound,
Figure BDA0000109325180000104
According to modification, the method also comprised by the stage forming below:
(iv) by the compound and the general formula R that obtain in the stage (ii) 4the chloro-formic ester reaction of-O-CO-Cl, wherein R 4as defined above, so that acquisition formula (V) compound,
Figure BDA0000109325180000111
According to another modification, if R 6and R 7form together covalent linkage, the method also can comprise with the next stage:
(v) incite somebody to action wherein R 6and R 7form together covalent linkage thereby by R 6and R 7form formula (I) compound oxidation of two keys, so that acquisition formula (VI) compound,
Figure BDA0000109325180000112
The present invention also relates to formula (I) compound as medicine.
The present invention also relates to pharmaceutical composition, it contains at least one formula (I) compound and pharmaceutically useful carrier as activeconstituents.
The present invention also relates to formula (I) compound for the preparation of the purposes of medicine that is used for the treatment of cancer.
Preferably, this medicine is used for the treatment of hormonal dependent cancer.
Preferably, this medicine is used for the treatment of the cancer of expressing androgen receptor.
Preferably, this medicine is used for the treatment of mammary cancer or prostate cancer, is preferably prostate cancer.
Accompanying drawing summary
Fig. 1 represents that the compound of embodiment 2 and 19 is not to containing the effect of the propagation of the LNCaP cell of cultivating in the substratum of steroide.
The effect of the minimizing of the protein expression of the compound of Fig. 2 to 9 expression embodiment 2,7,10,15,16,19,21 and 22 to androgen receptor.
Figure 10 represents the effect of the minimizing of the protein expression of Nilutamide to androgen receptor.
Invention embodiment describes in detail
Therefore, theme of the present invention is the compound of general formula (I),
Figure BDA0000109325180000121
Wherein R 1represent cyano group, nitro, amino ,-NHCOOR 4or-NHCOR 4group.
R 2represent halo, alkyl, haloalkyl, alkoxy base.R 3represent alkyl group or hydrogen.Alternatively, two R 3together with the carbon atom that group connects with them, form the group of naphthene base that comprises 3 to 4 members.
X represents to have the straight or branched alkylidene chain of 3 to 7 carbon atoms, and this chain can comprise one or more being selected from-O-,-N (R 5)-or-S-,-SO-or-SO 2-other identical or different member.Alternatively, X represents
Figure BDA0000109325180000122
group, wherein n1 and p1 are two integers, wherein n1+p1's and be included between 2 and 5.For example, n1 and p1 equal 1 or 2 separately, and preferably n1 and p1 equal 1.
R 6and R 7form together covalent linkage.In this case, X represents (CH 2) n1-CH=CH-(CH 2) p1 group.
Alternatively, R 6and R 7together with the carbon atom connecting with them, form
Figure BDA0000109325180000123
ring.According to another alternatives, R 6and R 7together with the carbon atom connecting with them, form the group of naphthene base that comprises 3 to 6 members, for example cyclobutyl, cyclopentyl or cyclohexyl.
R 4represent alkyl, aryl or heteroaryl groups.
R 5represent hydrogen, alkyl or aromatic alkyl group.
Formula (I) compound can be the form of pharmacologically acceptable salt.
So-called pharmacologically acceptable salt, refer in particular to mineral acid or organic acid additive salt, described mineral acid is hydrochloride, hydrobromate, vitriol, phosphoric acid salt, diphosphate and nitrate for example, and described organic acid is acetate, maleate, fumarate, tartrate, succinate, Citrate trianion, lactic acid salt, mesylate, benzene sulfonate, tosilate, pamoate and stearate for example.Within the salt (when they can be used) being formed by for example sodium hydroxide of alkali or potassium hydroxide is also included within scope of the present invention.For other example of pharmacologically acceptable salt, can be with reference to " Salt selection for basic drugs ", Int.J.Pharm. (1986), 33,201-217.
In definition shown in above, statement halogen (or halo) represents fluorine, chlorine, bromine or iodine group, is preferably chlorine, fluorine or bromine.
Except as otherwise noted, term alkyl within implication of the present invention represents the straight or branched alkyl group that comprises 1 to 12 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl and the tertiary butyl, amyl group or amyl group, isopentyl, neo-pentyl, hexyl or isohexyl, heptyl, octyl group, nonyl, decyl, undecyl or dodecyl group.Preferably, this alkyl group is (C 1-C 6) alkyl group, i.e. expression has the alkyl group of 1 to 6 carbon atom as defined above, or (C 1-C 4) alkyl group, expression has the alkyl group of 1 to 4 carbon atom, for example methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl and tertiary butyl groups.Most preferably, alkyl group is methyl group.
Term alkyl in statement alkoxyl group (or alkyl oxy) or haloalkyl represents alkyl group as defined above.
More specifically, so-called haloalkyl refers to alkyl group, and for example its at least one (and optionally all) hydrogen atom is substituted by halogen atom (halo), and is preferably trifluoromethyl.
Except as otherwise noted, so-called cycloalkyl refers to the saturated cyclic carbon-based group that contains 3 to 6 members, for example cyclopropyl or cyclobutyl.
In implication of the present invention, aromatic yl group can be monocycle or polycyclic aromatic type.Monocyclic aryl group can be selected from phenyl, tolyl, xylyl, mesityl (mesityl), cumenyl, is preferably phenyl group.Polyaromatic group can be selected from naphthyl, anthryl, phenanthryl, fluorenyl groups.They are optionally replaced by one or more identical or different groups for example alkyl, haloalkyl, alkoxyl group, alkoxy carbonyl, alkyl-carbonyl oxygen base, halo, cyano group, nitro, aryl, aryloxy, aryloxycarbonyl or aryl carbonyl oxygen base.
In implication of the present invention, term aralkyl represents the alkyl group as defined above by aromatic yl group replaces as defined above.
In implication of the present invention, term heteroaryl refers to and contains one or more identical or different heteroatomic unsaturated aromatic rings that are selected from N, O and S, for example furyl, thienyl, isoxazolyl, diazosulfide base, pyridyl, oxazolyl, pyrazolyl, pyrimidyl or quinoxalinyl.
Theme of the present invention is also the method for the preparation of formula (I) compound, and it comprised by the stage forming below:
(i) by the aryl glycolylurea of the general formula of two equivalents (II)
Figure BDA0000109325180000141
Wherein R 2and R 3as defined above, and R 1nitro or cyano group,
Under the existence of highly basic with general formula Gp 1-X-Gp 2derivative condensation, Gp 1and Gp 2be leavings group, and X is as defined above,
To form the compound of general formula (I),
Figure BDA0000109325180000142
Wherein R 2, R 3with X as defined above, and R 1nitro or cyano group.
A) R wherein 1the preparation of the compound of nitro or cyano group:
Can be according to the synthetic route preparation shown in lower Fig. 1 according to general formula of the present invention (I) compound.Wherein R 1, R 2, R 3can in a stage, obtain with X general formula as above (I) compound, pass through the aryl glycolylurea of the general formula of two equivalents (II) and general formula Gp 1-X-Gp 2derivative condensation, Gp 1and Gp 2be regarded as leavings group, and X as defined above, for example halogen group or sulfonate ester group.At alkali, for example NaH carries out condensation under existing.Preferably, by reaction mixture being heated to 20 to 100 ℃, preferably the temperature of 45 to 65 ℃ is carried out condensation.Preferably, polar solvent, preferably proton-inert polar solvent as THF, DMF or DMSO in condensation.Conventionally, the time length of 1 to 15 hours is carried out in reaction.
Figure BDA0000109325180000151
fig. 1
A.1) R wherein 1it is the preparation of amino compound
R therein 1nitro, R 2, R 3under X particular case as above, general formula (I) a1the preparation of anils be shown in figure A1.Use SnCl 22H 2o (J.Heterocyclic Chem.1987,24,927-930; Tetrahedron Letters 1984,25 (8), 839-842) at suitable solvent, carry out the reduction of nitryl group in as ethyl acetate.
Figure BDA0000109325180000152
figure A1
A.2) R wherein 1the preparation of the compound of ethanamide:
Wherein R 2, R 3, R 4with X general formula as above (I) a2acetamide derivative can be by general formula (I) a1anils through a stage, obtain, figure A2.Can use significantly excessive general formula R 4the acyl chlorides of-COCl is as Acetyl Chloride 98Min. or (R 4-CO) 2the acid anhydrides of O type is as diacetyl oxide and use this excessive reagent to carry out acylation reaction as solvent.
Figure BDA0000109325180000153
figure A2
A.3) R wherein 1the preparation of the compound of carbamate groups:
Wherein R 2, R 3, R 4with X general formula as above (I) a3carbamate derivatives by general formula (I) a1anils through a stage, prepare, figure A3.Use significantly excessive general formula R 4the chloro-formic ester of-O-CO-Cl, at anhydrous solvent, preferred anhydrous proton-inert polar solvent, under existing, carry out the formation of carbamate.Preferably, use anhydrous pyridine.Generally react by being heated to the temperature between 60 to 100 ℃ and reaching time length of 12 to 24 hours.
Figure BDA0000109325180000161
figure A3
The preparation of the compound that A.4) wherein X comprises oxyethane
At X, comprise two keys, R 1, R 2and R 3under particular case as above, general formula (I) a4compound can by for example peroxybenzoic acid of the oxygenant with suitable or peracetic acid in aprotic solvent, be oxidized general formula (I) compound obtain.Reaction is generally carried out and continues 1 to 4 day in envrionment temperature.
Figure BDA0000109325180000162
figure A4
B) preparation of the intermediate of general formula (II):
Wherein R 1, R 2and R 3the synthetic of the aryl glycolylurea intermediate of general formula as above (II) can carry out according to the strategy described in figure below:
B.1) by condensation, prepare aryl glycolylurea:
Can be by being used in alkali as K 2cO 3there is the lower general formula (II) producing 2the negatively charged ion nucleophilic substitution general formula (II) of glycolylurea 1the fluorine atom that has of the aromatic ring of compound, carry out aryl glycolylurea synthetic of general formula (II), figure B1.By the temperature between 65 to 140 ℃ with at polar aprotic solvent, heat in as DMF or DMSO and react.Temperature and reaction times are for highly depending on R 1and R 2the function of the freestone feature of the fluorine atom of character.The general formula (II) not being available commercially 2glycolylurea can for example, according to method preparation document (J.Med.Chem.1984,27 (12), 1663-8) Suo Shu.
Figure BDA0000109325180000171
figure B1
At R 1and R 2suction be electrically not enough in the situation of the aromatics nucleophilic substitution described in promotion figure B1, it is contemplated that neutralized verdigris exist under coupling aryl boric acid and general formula (II) 2the method (Synlett 2006,14,2290-2) of glycolylurea, to obtain the compound of general formula (II).
B.2) by building glycolylurea ring from aromatic isocyanate, prepare aryl glycolylurea:
In this case, according to Bioorg.Med.Chem.Lett.2004, the scheme described in 14,5285 is carried out the preparation of the glycolylurea of general formula (II).
B.3) by cyclisation, by aryl ureas, prepare aryl glycolylurea
Wherein R 1, R 2and R 3the synthetic of the aryl glycolylurea intermediate of general formula as above (II) can be by cyclisation for example, according to document (Organic Process Research & Development 2002,6,759-761) described in the general formula (II) prepared of method 3intermediate carry out, figure B3.Can be by forming the intermediate of carboxylic acid halides, then heating and carry out cyclization.Carboxylic acid halides can be produced by for example oxalyl chloride of halogenating agent or thionyl chloride in for example 1-4-diox of aprotic solvent or tetrahydrofuran (THF).
figure B3
B.4) by building glycolylurea ring from isocyanate amino esters, prepare aryl glycolylurea
Alternatively, as at Eur.J.Med.Chem.1984,19 (3), described in 261, the aryl glycolylurea of general formula (II) can be synthesized by isocyanate amino esters.
The salinization of formula (I) compound can be carried out by any method known to those skilled in the art.For example, salinization can be by adding alkali or acid, for example sodium hydroxide, potassium hydroxide or hydrochloric acid to carry out.
According to formula of the present invention (I) compound, there is available pharmacological properties.In fact, found that formula of the present invention (I) compound has antitumor (anticancer) activity, and more specifically had the cell of expression androgen receptor as the inhibition activity of the cell proliferation of LnCAP type prostatic cell.Therefore, compound of the present invention can be used for different treatment application.They can be advantageously used in treatment cancer, particularly hormonal dependent cancer, express the cancer of androgen receptor, and more especially mammary cancer and prostate cancer.The example of the pharmacological properties of the compounds of this invention is found in following experimental section.
Therefore, the application's theme is also the formula as medicine (I) compound as defined above.
Equally, the application's theme is the formula as medicine (I) compound as defined above, this medicine is used for the treatment of proliferative disease, preferably cancer, more preferably hormonal dependent cancer or express the cancer of androgen receptor, or also treats prostate cancer and mammary cancer, more preferably prostate cancer.
The application's theme is also pharmaceutical composition, and it comprises at least one formula (I) compound and pharmaceutically useful carrier as defined above as activeconstituents.
The application's theme is also the purposes for the preparation of antitumor drug according to formula of the present invention (I) compound.
The application's theme is also the purposes for the preparation of medicine according to formula of the present invention (I) compound, and this medicine is used for suppressing cell proliferation.
The application's theme is also the purposes for the preparation of medicine according to formula of the present invention (I) compound, this medicine is used for the treatment of proliferative disease, preferably cancer, very preferably hormonal dependent cancer or express the cancer of androgen receptor, or prostate cancer and mammary cancer, prostate cancer very preferably.
Pharmaceutical composition can be the form of solid, for example powder, particle, tablet, gelatine capsule.Suitable solid carrier can be for example calcium phosphate, Magnesium Stearate, talcum, sugar, lactose, dextrin, starch, gelatin, Mierocrystalline cellulose, methylcellulose gum, sodium carboxy methyl cellulose, polyvinylpyrrolidine and wax.
The pharmaceutical composition that contains the compounds of this invention also can exist by liquid form, for example solution, emulsion, suspension or syrup.Suitable liquid vehicle can be for example for example glycerine of water, organic solvent or ethylene glycol and be added to pharmaceutically useful oil or their mixtures in water in varing proportions of fat.Sterile liquid composition can be used for intramuscular, intraperitoneal or subcutaneous injection, and aseptic composite also can be used by intravenous route.
All technology used herein and scientific terminology have implication well known by persons skilled in the art.And all patents (or patent application) and other are recorded document mode by reference and are incorporated to.
experimental section
According to variable R 1, R 2, R 3with the definition of X, can be according to above-mentioned different methods preparation according to compound of the present invention.
The NMR that carries out embodiment 1 to 23 on 400MHz Bruker-Avance II spectrograph analyzes.
Provide embodiment so that illustration aforesaid method, and these embodiment are never interpreted as limitation of the scope of the invention.
In the nomenclature of following compound and embodiment, term used is IUPAC term.
embodiment 1: 1,1 '-butane-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
Under argon gas, by NaH (60%) (22mg, 0.55mmol) add to 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] solution of-imidazolidine-2,4-dione (158mg, 0.5mmol) in dry DMF (8ml).The release of gas is accompanied by the variation of reaction medium color, becomes orange.At 23 ℃, maintain and stir 30 minutes, then add Isosorbide-5-Nitrae-dibromobutane (30 μ l, 0.25mmol).55 ℃ of heating 1 hour, then pour reaction mixture into NH 4cl saturated aqueous solution (25ml), with AcOEt extraction (2x25ml).Organic phase is merged, continuously water (25ml) and salt solution (25ml) washing.Through Na 2sO 4after dry, filter organic solution, concentrated under vacuum.Through silicon-dioxide column purification evaporation residue (eluent: heptane/AcOEt:4/6 to 1/9).
The expecting compound that obtains light yellow solid form, yield is 45%.Fusing point: 211-212 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,32(d，2H，Ph)；8,21(d，2H，Ph)；8,08(dd，2H，Ph)；3,39(m，4H，2?x?NCH 2)；1,70(m，4H，2?x?CH 2)；1,49(s，12H，4?x?CH 3).
embodiment 2: 1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
Synthetic described identical with for embodiment 1 compound of experimental program used, 1,5-, bis-iodopentanes substitute Isosorbide-5-Nitrae-dibromobutane.The expecting compound that obtains white solid form, yield is 40%.Fusing point: 163-164 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,33(d，2H，Ph)；8,21(d，2H，Ph)；8,07(d，2H，Ph)；3,34(m，4H，2?x?NCH 2)；1,69(m，4H，2?x?CH 2)；1,50(s，12H，4?x?CH 3)；1,41(m，2H，CH 2).
embodiment 3: 1,1 '-hexane-1,6-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
Synthetic described identical with for embodiment 1 compound of experimental program used, 1,6-, bis-iodohexanes substitute Isosorbide-5-Nitrae-dibromobutane.The expecting compound that obtains light yellow solid form, yield is 27%.Fusing point: 187-188 ℃.
1h NMR 400MHz (DMSO-d 6) δ: 8.31 (wide bimodal, 2H, Ph); 8.20 (wide unimodal, 2H, Ph); 8.07 (wide bimodal, 2H, Ph); 3.32 (m, 4H, 2 x NCH 2); 1.64 (m, 4H, 2 x CH 2); 1.46 (s, 12H, 4 x CH 3); 1.38 (m, 4H, 2 x CH 2).
embodiment 4: 1,1 '-heptane-1,7-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
Synthetic described identical with for embodiment 1 compound of experimental program used, 1,7-dibromo-heptane substitutes Isosorbide-5-Nitrae-dibromobutane.The expecting compound that obtains light yellow solid form, yield is 35%.Fusing point: 137-138 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,31(d，2H，Ph)；8,19(d，2H，Ph)；8,06(dd，2H，Ph)；3,30(m，4H，2?x?NCH 2)；1,64(m，4H，2?x?CH 2)；1,46(s，12H，4?x?CH 3)；1,36(m，6H，3?x?CH 2).
embodiment 5: 4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
5.1) 4-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-(trifluoromethyl) benzonitrile
By fluoro-4-2-(trifluoromethyl) benzonitrile (5.67g, 30mmol), 5,5-dimethyl-glycolylurea (7.68g, 60mmol), K 2cO 3(8.28g, 60mmol) mixture in DMF (45ml) is equally dispensed in three pipes to be placed in microwave oven.Under magnetic agitation, by each pipe 140 ℃ of radiation 20 minutes.Then reactive material is merged, be poured into water (200ml), with AcOEt extraction (2x75ml).Merge organic phase, use salt water washing, through Na 2sO 4dry, filter.Under reduced pressure concentrated filtrate, resistates is from Et 2o (25ml) crystallization.From EtOH (75ml) recrystallization, filtering powder, dry under vacuum.The expecting compound that obtains white solid form, yield is 46% (4.1g).Fusing point: 212-213 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,80(s，1H，NH)；8,29(d，1H，Ph)；8,18(s，1H，Ph)；8,02(d，1H，Ph)；1,42(s，6H，2?x?CH 3).
5.2) 4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
Synthetic described identical with for embodiment 2 compounds of experimental program used, intermediate 5.1 substitutes 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-imidazolidine-2,4-dione.The expecting compound that obtains white solid form, yield is 50% (330mg).Fusing point: 167-169 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,28(d，2H，Ph)；8,18(s，2H，Ph)；8,02(d，2H，Ph)；3,30(m，4H，2?x?NCH 2)；1,67(m，4H，2?x?CH 2)；1,46(s，12H，4?x?CH 3)；1,40(m，2H，CH 2).
embodiment 6: 1,1 '-(3-methylpentane-1,5-bis-bases) 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }
Synthetic described identical with for embodiment 1 compound of experimental program used, the bromo-3-methylpentane of 1,5-bis-substitutes Isosorbide-5-Nitrae-dibromobutane.Obtain the expecting compound of light yellow foam form, yield is 39%.
1H?NMR?400MHz(DMSO-d 6)δ：8,30(d，2H，Ph)；8,20(d，2H，Ph)；8,07(dd，2H，Ph)；3,38(m，4H，2?x?NCH 2)；1,72(m，4H，2?x?CH 2)；1,53(m，1H，CH)；1,49(s，12H，4?x?CH 3)；1,00(d，3H，CH 3).
embodiment 7: 1,1 '-(oxygen base two ethane-2,1-bis-bases) 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
Synthetic described identical with for embodiment 1 compound of experimental program used, two-(2-bromotrifluoromethane) ethers substitute Isosorbide-5-Nitrae-dibromobutane.The expecting compound that obtains white solid form, yield is 70%.Fusing point: 186-188 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,28(d，2H，Ph)；8,16(d，2H，Ph)；8,03(dd，2H，Ph)；3,67(t，4H，2?x?CH 2)；3,52(t，4H，2?x?CH 2)；1,47(s，12H，4?x?CH 3).
embodiment 8: 1,1 '-pentane-1,5-bis-bases two 3-[4-amino-3-(trifluoromethyl) phenyl] and-5,5-methylimidazole alkane-2,4-diketone }
By embodiment 2 compound (410mg, 0.58mmol) and SnCl 22H 2the mixture of O (1.32g, 5.8mmol) in AcOEt (10ml) was 80 ℃ of heating 90 minutes.Then reaction medium is cooled to 0 ℃, then pours Na into 2cO 3saturated aqueous solution (40ml).Thus obtained Inhomogeneous charge thing, through diatomite filtration, is used to AcOEt rinsing (2x50ml).After decantation, organic phase is merged, through Na 2sO 4dry, filter, by solvent vapourisation under reduced pressure.Gained resistates is dissolved in the mixture of heptane/AcOEt, to generate white solid, after filtration, yield is 78% (290mg).Fusing point: 108-109 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：7,32(d，2H，Ph)；7,23(dd，2H，Ph)；6,85(d，2H，Ph)；5,80(s，4H，2?x?NH 2)；3,27(m，4H，2?x?NCH 2)；1,64(m，4H，2?x?CH 2)；1,40(s，12H，4?x?CH 3)；1,31(m，2H，CH 2).
embodiment 9: N, N '-(pentane-1,5-bis-bases two { (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases) [2-(trifluoromethyl)-4,1-phenylene] }) diethylamide
Under argon atmospher, embodiment 8 compounds (161mg, 0.25mmol) are mixed with Acetyl Chloride 98Min. (10ml), at 23 ℃, stirring is maintained to 15 hours.Then reaction mixture is evaporated to dry (carrying toluene secretly), by gained resistates through silicon-dioxide column purification (eluent: CH 2cl 2/ EtOH from 99/1 to 90/10).After evaporation, obtain the expecting compound of cream-colored foam form, yield is 52%.
1H?NMR?400MHz(DMSO-d 6)δ：9,63(s，2H，CONH)；7,81(d，2H，Ph)；7,69(dd，2H，Ph)；7,58(d，2H，Ph)；3,30(m，4H，2?x?NCH 2)；2,06(s，6H，2?x?CH 3)；1,67(m，4H，2?x?CH 2)；1,40(s，12H，4?x?CH 3)；1,40(m，2H，CH 2).
embodiment 10: 1,1 '-pentane-1,5-bis-bases two [5,5-dimethyl-3-(3-methyl-4-nitrophenyl)-imidazolidine-2,4-dione]
10.1) 5,5-dimethyl-3-(3-methyl-4-nitrophenyl) imidazolidine-2,4-dione
By 5-fluorine-2-nitro methylbenzene (1.55g, 10mmol), 5,5-T10 (1.28g, 10mmol), K 2cO 3(1.38g, 10mmol) mixture in DMF (15ml) is put into expection and is placed in the pipe of microwave oven, in 100 ℃ of radiation 70 minutes under magnetic agitation.Then reaction mixture is poured in water (200ml), with AcOEt extraction (2x75ml).Merge organic phase, use salt water washing, through Na 2sO 4dry, filter.Under reduced pressure concentrated filtrate, by silica column chromatography purification resistates (eluent: heptane/AcOEt:7/3).The expecting compound that obtains white solid form, yield is 25% (666mg).Fusing point: 177-178 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,70(s，1H，NH)；8,10(d，1H，Ph)；7,58(s，1H，Ph)；7,52(dd，1H，Ph)；2,54(s，3H，CH 3)；1,41(s，6H，2?x?CH 3).
10.2) 1,1 '-pentane-1,5-bis-bases two [5,5-dimethyl-3-(3-methyl-4-nitrophenyl)-imidazolidine-2,4-dione]
Synthetic described identical with for embodiment 2 compounds of experimental program used, intermediate 10.1 substitutes 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl]-imidazolidine-2,4-dione.The expecting compound that obtains white solid form, yield is 67% (495mg).Fusing point: 130-131 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,09(d，2H，Ph)；7,58(s，2H，Ph)；7,52(dd，2H，Ph)；3,32(s，4H，2?x?NCH 2)；2,53(s，6H，2?x?CH 3)；1,68(m，4H，2?x?CH 2)；1,46(s，12H，4?x?CH 3)；1,38(m，2H，CH 2).
embodiment 11: 1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-2-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
11.1) 5,5-dimethyl-3-[4-nitro-2-(trifluoromethyl) phenyl] imidazolidine-2,4-dione
Synthetic described identical with for intermediate 10.1 of experimental program used, 2-fluoro-5-nitro trifluor toluene substitutes 5-fluorine-2-nitro methylbenzene.The expecting compound that obtains white solid form, yield is 29%.Fusing point: 175-176 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,76(s，1H，NH)；8,68(dd，1H，Ph)；8,58(d，1H，Ph)；8,04(d，1H，Ph)；1,47(s，3H，CH 3)；1,38(s，3H，CH 3).
11.2) 1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-2-(trifluoromethyl) phenyl]-imidazolidine-2,4-dione }
Synthetic described identical with for embodiment 2 compounds of experimental program used, intermediate 11.1 substitutes 5,5-dimethyl-3-[4-nitro--3-(trifluoromethyl) phenyl]-imidazolidine-2,4-dione.Obtain the expecting compound of light yellow foam form, yield is 12%.
1H?NMR?400MHz(DMSO-d 6)δ：8,68(m，2H，Ph)；8,58(d，2H，Ph)；8,04(d，2H，Ph)；3,33(m，4H，2?x?NCH 2)；1,66(m，4H，2?x?CH 2)；1,50(m，6H，2?x?CH 3)；1,42(m，6H，2?x?CH 3)；1,35(m，2H，CH 2).
embodiment 12: 1,1 '-pentane-1,5-bis-bases two [3-(3-chloro-4 nitrophenyl)-5,5-dimethyl-imidazolidine-2,4-dione]
12.1) 3-(3-chloro-4 nitrophenyl)-5,5-methylimidazole alkane-2,4-diketone
Experimental program used is identical with the synthetic described scheme for intermediate 10.1, and the chloro-4-fluoronitrobenzene of 2-substitutes 5-fluorine-2-nitro methylbenzene.The expecting compound that obtains faint yellow solid form, yield is 28%.Fusing point: 144-145 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,77(s，1H，NH)；8,21(d，1H，Ph)；7,92(d，1H，Ph)；7,71(dd，1H，Ph)；1,41(s，6H，2?x?CH 3).
12.2) 1,1 '-pentane-1,5-bis-bases two [3-(3-chloro-4 nitrophenyl)-5,5-methylimidazole alkane-2,4-diketone]
Synthetic described identical with for embodiment 2 compounds of experimental program used, intermediate 12.1 substitutes 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-imidazolidine-2,4-dione.Obtain the expecting compound of light yellow foam form, yield is 7%.
1H?NMR?400MHz(DMSO-d 6)δ：8,28(d，2H，Ph)；7,99(d，2H，Ph)；7,79(dd，2H，Ph)；3,37(m，4H，2?x?NCH 2)；1,74(m，4H，2?x?CH 2)；1,53(m，12H，4?x?CH 3)；1,46(m，2H，CH 2).
embodiment 13: 1,1 '-pentane-1,5-bis-bases two [3-(3-methoxyl group-4-nitrophenyl)-5,5-dimethyl-imidazolidine-2,4-dione]
13.1) 3-(3-methoxyl group-4-nitrophenyl)-5,5-methylimidazole alkane-2,4-diketone
Experimental program used is identical with the synthetic described scheme for intermediate 10.1, and the fluoro-2-Nitroanisole of 5-substitutes 5-fluorine-2-nitro methylbenzene.The expecting compound that obtains white solid form, yield is 20%.
1H?NMR?400MHz(DMSO-d 6)δ：8,70(s，1H，NH)；7,99(d，1H，Ph)；7,47(d，1H，Ph)；7,20(dd，1H，Ph)；3,91(s，3H，OCH 3)；1,42(s，6H，2?x?CH 3).
13.2) 1,1 '-pentane-1,5-bis-bases two [3-(3-methoxyl group-4-nitrophenyl)-5,5-dimethyl-imidazolidine-2,4-dione]
Synthetic described identical with for embodiment 2 compounds of experimental program used, intermediate 13.1 substitutes 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl]-imidazolidine-2,4-dione.The expecting compound that obtains white foam shape thing form, yield is 10%.
1H?NMR?400MHz(DMSO-d 6)δ：8,07(d，2H，Ph)；7,54(d，2H，Ph)；7,28(dd，2H，Ph)；3,97(s，6H，2?x?OCH 3)；3,38(m，4H，2?x?NCH 2)；1,74(m，4H，2?x?CH 2)；1,53(m，12H，4?x?CH 3)；1,46(m，2H，CH 2).
embodiment 14: { pentane-1,5-bis-bases two [(4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases) (2-methyl-4,1-phenylene)] } diamino acid dimethyl ester
14.1) 1,1 '-pentane-1,5-bis-bases two [3-(4-amino-3-aminomethyl phenyl)-5,5-dimethyl-imidazolidine-2,4-dione]
Experimental program used is identical with the synthetic described scheme for embodiment 8 compounds, by embodiment 10 compounds, starts alternate embodiment 2 compounds.The expecting compound that obtains white foam shape thing form, yield is 69%.
1H?NMR?400MHz(DMSO-d 6)δ：6,79(m，4H，Ph)；6,60(d，2H，Ph)；5,02(s，4H，2?x?NH 2)；3,26(m，4H，2?x?NCH 2)；2,03(s，6H，2?x?CH 3)；1,62(m，4H，2?x?CH 2)；1,39(s，12H，4?x?CH 3)；1,31(m，2H，CH 2).
14.2) { pentane-1,5-bis-bases two [(4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases) (2-methyl-4,1-phenylene)] } diamino acid dimethyl ester
Under argon atmospher, will be dissolved in intermediate 14.1 (268mg, 0.5mmol) in anhydrous pyridine (10ml) and mix with methyl-chloroformate (0.8ml, 10mmol).At 90 ℃, maintain and stir 18 hours.Then reaction mixture is poured in frozen water, with AcOEt extraction (2x50ml).Organic phase is merged, with salt solution (25ml) washing.By organic solution through Na 2sO 4dry, filter vapourisation under reduced pressure solvent.Through silicon-dioxide column purification resistates (eluent: heptane/AcOEt:4/6 to 0/1).The expecting compound that obtains white foam shape thing form, yield is 40% (130mg).
1H?NMR?400MHz(DMSO-d 6)δ：8,92(s，2H，NH)；7,43(d，2H，Ph)；7,17(d，2H，Ph)；7,12(dd，2H，Ph)；3,66(s，6H，2?x?OCH 3)；3,29(m，4H，2?x?NCH 2)；2,20(s，6H，2?x?CH 3)；1,66(m，4H，2?x?CH 2)；1,42(s，12H，4?x?CH 3)；1,37(m，2H，CH 2).
embodiment 15: 4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-methyl benzonitriles)
15.1) 4-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl)-2-methyl benzonitrile
Experimental program used is identical with the synthetic described scheme for intermediate 5.1, and the fluoro-2-methyl of 4-benzonitrile substitutes the fluoro-2-of 4-(trifluoromethyl) benzonitrile.From EtOH (75ml) recrystallization, obtain the expecting compound of white solid form, yield is 5%.
1H?NMR?400MHz(DMSO-d 6)δ：8,70(s，1H，NH)；7,89(d，1H，Ph)；7,54(s，1H，Ph)；7,43(d，1H，Ph)；2,49(s，3H，CH 3)；1,40(s，6H，2?x?CH 3).
15.2) 4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-methyl benzonitriles)
Synthetic described identical with for embodiment 2 compounds of experimental program used, intermediate 15.1 substitutes 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl]-imidazolidine-2,4-dione.The expecting compound that obtains white solid form, yield is 66%.Fusing point: 148-149 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：7,81(d，2H，Ph)；7,49(d，2H，Ph)；7,39(dd，2H，Ph)；3,30(m，4H，2?x?NCH 2)；2,43(s，6H，2?x?CH 3)；1,62(m，4H，2?x?CH 2)；1,39(s，12H，4?x?CH 3)；1,31(m，2H，CH 2).
embodiment 16: 4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-benzyl chloride nitriles)
16.1) the chloro-4-of 2-(4,4-dimethyl-2,5-dioxo alkyl imidazole-1-yl) benzonitrile
Embodiment used is with identical for the scheme described in intermediate 5.1, and the chloro-4-fluorine of 2-benzonitrile substitutes the fluoro-2-of 4-(trifluoromethyl) benzonitrile.The expecting compound that obtains white solid form, yield is 23%.
1H?NMR?400MHz(DMSO-d 6)δ：8,76(s，1H，NH)；8,08(d，1H，Ph)；7,90(d，1H，Ph)；7,67(dd，1H，Ph)；1,40(s，6H，2?x?CH 3).
16.2) 4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-benzyl chloride nitriles)
Synthetic described identical with for embodiment 2 compounds of experimental program used, intermediate 16.1 substitutes 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl]-imidazolidine-2,4-dione.The expecting compound that obtains white solid form, yield is 51%.Fusing point: 166-167 ℃.
1H?NMR?400MHz(DMSO-d 6)δ：8,08(d，2H，Ph)；7,90(d，2H，Ph)；7,68(dd，2H，Ph)；3,30(m，4H，2?x?NCH 2)；1,64(m，4H，2?x?CH 2)；1,45(s，12H，4?x?CH 3)；1,38(m，2H，CH 2).
embodiment 17:1,1 '-propane-1,3-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
Synthetic described identical with for embodiment 1 compound of experimental program used, 1,3-diiodo propane substitutes Isosorbide-5-Nitrae-dibromobutane.The expecting compound that obtains white solid form, yield is 15% (50mg).Fusing point: 164-165 ℃.
1H?NMR?400MHz(DMSO-
Figure BDA0000109325180000271
)
Figure BDA0000109325180000272
8,33(d，2H，Ph)；8,21(d，2H，Ph)；8,09(dd，2H，Ph)；3,45(t，4H，2?x?NCH 2)；2,01(m，2H，CH 2)；1,50(s，12H，4?x?CH 3).
embodiment 18: 2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl]-2,4-dioxo alkyl imidazole-1-yl }-N-(2-{5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-2,4-dioxo alkyl imidazole-1-yl } ethyl)-N-methyl chlorination second ammonium
Synthetic described identical with for embodiment 1 compound of experimental program used, mustine hydrochlcride substitutes Isosorbide-5-Nitrae-dibromobutane.The expecting compound that obtains light yellow solid form, yield is 30%.Fusing point: 136-137 ℃.
1h NMR 400MHz (DMSO-d 6) δ: 11.08 (wide unimodal, 1H, NH +); 8.31 (m, 4H, Ph); 8.10 (d, 2H, Ph); 3.87 (m, 4H, 2 x NCH 2); 3.51 (m, 2H, NCH 2); 3.38 (m, 2H, NCH 2); 2.99 (wide unimodal, 3H, CH 3); 1.55 (s, 12H, 4 x CH 3).
embodiment 19: 1,1 '-(2Z)-but-2-ene-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }
Synthetic described identical with for embodiment 1 compound of experimental program used, cis-Isosorbide-5-Nitrae-dichloro-2-butene substitutes Isosorbide-5-Nitrae-dibromobutane.The expecting compound that obtains faint yellow solid form, yield is 40%.Fusing point: 191-193 ℃.
1H?NMR?400MHz(DMSO-
Figure BDA0000109325180000273
)
Figure BDA0000109325180000274
：8,34(d，2H，Ph)；8,22(d，2H，Ph)；8,09(dd，2H，Ph)；5,61(q，2H，CH＝CH)；4,2(q，4H，2?x?CH 2)；1,50(s，12H，4?x?CH 3).
embodiment 20: 4,4 '-[pentane-1,5-bis-bases two (5,7-dioxo-4,6-diaza spiro [2.4] heptane-4,6-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
20.1) 1-({ [4-cyano group-3-(trifluoromethyl) phenyl] formamyl } amino) cyclopropane-carboxylic acid
By 4-isocyanide acyl group-2-(trifluoromethyl) benzonitrile (4.56g; 21.5mmol) solution in acetone (12ml) drops to and is dissolved in aqueous sodium hydroxide solution (12ml; 0.8g; 1-amino-cyclopropane formic acid (2.02g, 20mmol) 20mmol).Reaction medium is stirred 1 hour in envrionment temperature, then pour (1N, 40ml) in aqueous sodium hydroxide solution into.By gained ethyl acetate (30ml) washing for solution, then, by adding aqueous sulfuric acid (2M, 30ml) acidifying, be extracted with ethyl acetate (2x50ml).Thus obtained organic phase water, then with saturated sodium-chloride water solution washing, through Na 2sO 4dry, filter.Vapourisation under reduced pressure solvent.Gained resistates is dissolved in ether to generate white solid.After filtration, yield is 50% (3.16g).
20.2) 4-(5,7-dioxo-4,6-diaza spiro [2.4] heptan-6-yl)-2-(trifluoromethyl) benzonitrile
Under argon gas, oxalyl chloride (1.12ml, 13mmol) is added to intermediate 20.1 (3.16g, 10mmol) and the solution of DMF (0.5ml) in Isosorbide-5-Nitrae-dioxs (20ml).Reaction medium is stirred 1 hour under refluxing to vapourisation under reduced pressure solvent.Resistates is dissolved in water (30ml), by gained ethyl acetate (50ml) extraction for solution.By continuous organic phase water and saturated nacl aqueous solution washing, through Na 2sO 4dry.Vapourisation under reduced pressure solvent.Gained resistates is dissolved in ether to generate white solid, and after filtration, yield is 20% (0.6g).
1h NMR 400MHz (DMSO-
Figure BDA0000109325180000281
)
Figure BDA0000109325180000282
: 8,91 (s, 1H, NH); 8,27 (d, 1H, Ph); 8,18 (s, 1H, Ph); 8,04 (d, 1H, Ph); 1,3-1,45 (m, 4H, 2 x CH 2spiral shell).
20.3) 4,4 '-[pentane-1,5-bis-bases two (5,7-dioxo-4,6-diaza spiro [2.4] heptane-4,6-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
Synthetic described identical with for embodiment 2 compounds of experimental program used, intermediate 20.2 substitutes 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-imidazolidine-2,4-dione.Obtain the expecting compound of white solid form.Fusing point: 154-155 ℃.
1h NMR 400MHz (DMSO-
Figure BDA0000109325180000283
) δ: 8,27 (d, 2H, Ph); 8,17 (d, 2H, Ph); 8,03 (dd, 2H, Ph); 3,14 (t, 4H, CH 2x 2); 1.64 (m, 4H, 2 x CH 2); 1,55 (m, 4H, 2 x CH 2spiro); 1,36 (m, 6H, CH 2centre, 2 x CH 2spiral shell).
embodiment 21: 4,4 '-[(2Z)-but-2-ene-Isosorbide-5-Nitrae-bis-base two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two [2-(trifluoromethyl) benzonitriles]
Experimental program used is identical with the synthetic described scheme for embodiment 1, cis-Isosorbide-5-Nitrae-dichloro-2-butene substitutes Isosorbide-5-Nitrae-dibromobutane and intermediate 5.1 substitutes 5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl]-imidazolidine-2,4-dione.Obtain the expecting compound of oldlace solid form.Fusing point: 188-190 ℃.
1H?NMR?400MHz(DMSO-d 6)
Figure BDA0000109325180000291
：8,32(d，2H，Ph)；8,19(d，2H，Ph)；8,05(dd，2H，Ph)；5,60(q，2H，CH＝CH)；4,2(q，4H，2?x?CH 2)；1,49(s，12H，4?x?CH 3).
embodiment 22: 4,4 '-{ (2R, 3S)-oxyethane-2,3-bis-bases two [methane two bases (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] } two [2-(trifluoromethyl) benzonitriles]
Under argon gas, embodiment 21 compounds (90mg, 0.139mmol) and 3-metachloroperbenzoic acid (72.5mg, 0.210mmol) are mixed in anhydrous methylene chloride (10ml).Mixture is stirred in envrionment temperature.The process of reaction is by TLC (eluent DCM/EtOH:95/05) monitoring.After 4 days, initial compounds still has residual.The metachloroperbenzoic acid (0.124g, 0.36mmol) of new system is added in reaction medium, and reaction medium is stirred 4 days in envrionment temperature again.Vapourisation under reduced pressure solvent, resistates is by purified by flash chromatography (BIOTAGE 25+M post, gradient methylene dichloride/acetone: 0% to 8% acetone).The expecting compound that obtains white solid form, yield is 50%.Fusing point: 108-110 ℃.
1H?NMR?400MHz(DMSO-)
Figure BDA0000109325180000292
Figure BDA0000109325180000293
：8,32(d，2H，Ph)；8,21(d，2H，Ph)；8,05(dd，2H，Ph)；4,05(q，2H，CH-CH)；3.28(m，4H，2?x?CH 2)；1,53(d，12H，4?x?CH 3).
embodiment 23:4,4 '-{ (1R, 2R)-cyclopropane-1,2-bis-bases two [methane two bases (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] } two [2-(trifluoromethyl) benzonitriles]
Synthetic described identical with for embodiment 1 compound of experimental program used, anti-form-1, and 2-bis-(brooethyl) cyclopropane (according to J.Med.Chem.2003,46 (21), 4586-4600 preparation) alternative Isosorbide-5-Nitrae-dibromobutane.Obtain the expecting compound of cream-colored solid form.Fusing point: 178-180 ℃.
1H?NMR?400MHz(DMSO-
Figure BDA0000109325180000294
)δ：8,26(d，2H，Ph)；8,15(d，2H，Ph)；8,01(dd，2H，Ph)；3,2-3,4(m，4H，2?x?NCH 2)；2,49(s，12H，4?x?CH 3)；1,24(m，2H，2?x?CH)；0,61(t，2H，1x?CH 2).
according to the pharmaceutical research of compound of the present invention
the measurement of antiproliferative activity:
1. to the antiproliferative activity of the LNCaP in perfect medium
By applying following experimental arrangement, measure the antiproliferative activity of the compounds of this invention to the LNCaP in perfect medium:
LNCaP cell type (ATCC, 1740) is derived from the prostate cancer of expressing androgen receptor, and this clone is hormonal dependent.
In following perfect medium, carry out the maintenance of LNCaP system: RPMI, 10% foetal calf serum, 2mM glutamine, 100U/ml penicillin, 0.1mg/ml Streptomycin sulphate and 0.01M HEPES, 1mM Sodium.alpha.-ketopropionate, 40%D-glucose.
● inoculation is dull and stereotyped: in the 96-hole flat board (Biocoat, Costar) that scribbles poly--D-Lys, with 20,000 cells/well, in 90 μ l perfect mediums, inoculate LNCaP system.
● process cell: inoculate latter 24 hours, be diluted in the compound treatment cell in substratum with 10 μ l/ holes.Concentration used is as follows: 1nM/10/30/100/300/1000/3000/10,000/100,000nM.By cell at 37 ℃, 5% CO 2under hatch 144 hours.
● reading: hatch after 6 days, 10 μ L " WST-1 cell proliferation " reagent (Roche ref1644807) are added in each hole.At 37 ℃, 5%CO 2hatch after 2 hours, by spectrophotometry (Envision, Perkin Elmer), measure the absorbancy at 450nm.
● result: test in duplicate, by twice of best compound test.Calculate the concentration value (IC that suppresses cell proliferation 50% 50).
The IC of all compounds of the above embodiments 1 to 23 to the LNCaP cell in culture 50be less than or equal to 5000nM.
Wherein, the IC of the compound of following examples to the LNCaP cell in culture 50be less than 1500nM:1,2,4,7,10,13,14,15,16,19,20,21 and 22.
The IC of the compound of following examples to the LNCaP cell in culture 50be less than 500nM:1,2,7,15,19,20,21 and 22.
2. pair lack the antiproliferative activity of the LNCaP in the substratum of steroide:
Measure the compounds of this invention to lacking short propagation and/or the antiproliferative activity of the LNCaP in the substratum of steroide.
LNCaP clone (ATCC, 1740) is derived from the prostate cancer of expressing androgen receptor, and this clone is hormonal dependent.
In RPMI, 10% foetal calf serum, 2mM glutamine, 100U/ml penicillin, 0.1mg/ml Streptomycin sulphate and 0.01M HEPES, 1mM Sodium.alpha.-ketopropionate, 40%D-glucose, under usual conditions, carry out the maintenance of LNCaP system.
For not containing the research under the condition of steroide, at the front substratum of removing cell for 24 hours of inoculation.Use PBS washed cell, then containing phenol red RPMI substratum, 10% foetal calf serum (using in advance the processing of charcoal-dextran), 2mM glutamine, 100U/ml penicillin, 0.1mg/ml Streptomycin sulphate and the 0.01M HEPES that do not contain steroide, 1mM Sodium.alpha.-ketopropionate, 40%D-glucose, under existing, do not hatching.
● inoculation is dull and stereotyped:
In the 96-hole flat board (Biocoat, Costar) that scribbles poly--D-Lys, with 20,000 cells/well inoculation LNCaP system in 90 μ l RPMI (containing 10% foetal calf serum, not containing steroide).
● process cell: inoculate latter 24 hours, be diluted in the compound treatment cell in substratum with 10 μ l/ holes.Concentration used is as follows: 1nM/10/30/100/300/1000/3000/10,000/100,000nM.By cell at 37 ℃, 5%CO 2under hatch 144 hours.
● reading: hatch after 6 days, 10 μ L " WST-1 cell proliferation " reagent (Roche ref1644807) are added in each hole.At 37 ℃, 5%CO 2hatch after 2-4 hour, by spectrophotometry (Envision, Perkin Elmer), measure the absorbancy at 450nm.
● result: test in duplicate, by twice of best compound test.Calculate the concentration value (IC that suppresses cell proliferation 50% 50).
(Veldscholte J, Berrevoets CA, Brinkmann AO, Grootegoed JA, Mulder E.Biochemistry on March 3rd, 1992 as mentioned above; 31 (8): 2393-9), Nilutamide shows has agonist activity when lower concentration, and have when high density, suppresses active.
Surprisingly, the LNCaP that 1 to 23 pair of compound lacks in the substratum of steroide does not have agonist effect.And, when compound 2 and 19 is presented at lower concentration, significantly suppress active.
Fig. 1 illustrates the effect of the cell proliferation of 2 and 19 couples of LNCaP that cultivate in the substratum that lacks steroide of compound.
3. the measurement of the protein expression of androgen receptor
With the speed of 2,500,000 cell/10cm culture dish, in RPMI, 10% foetal calf serum, 2mM glutamine, 100U/ml penicillin, 0.1mg/ml Streptomycin sulphate and 0.01M HEPES, 1mM Sodium.alpha.-ketopropionate, 40%D-glucose, inoculate the cell of LNCaP system.After 4 days, with compound treatment cell to be tested.Process latter 72 hours, by cytolysis in lysis buffer (50mM Tris pH 7.4,150mM NaCl, 1mM EDTA, 20mM NaF, 100mM Na 2vO 3, 0.5% NP40,1% Triton X-100,1mM EGTA, Pefabloc, proteinase inhibitor mixture 11836170001RocheDiagnostics, inhibitors of phosphatases mixture II organizes Calbiochem) in.Then scraping cell, by lysate be transferred in QIA pulverizer pipe (catalog number (Cat.No.) 79656 Qiagen) for 4 ℃ with 13,000rpm centrifugal 15 minutes.Supernatant liquor is transferred in QIA pulverizer pipe for carry out 5 minutes centrifugal for the second time with 13,000rpm, to remove DNA filament completely.Then measure protein concn (Bio-Rad DC protein determination test kit), through regulating the protein/hole (10 μ g and 20 μ g/ holes, depend on experiment) with load equivalent.The sample-loading buffer (sample sample-loading buffer 3X ref 7722 Cell signalling techniques) that is added with 1% beta-mercaptoethanol and 50mMDTT is added in sample, then 90 ℃ of heating 10 minutes.Sample is stored on NuPAGE 4-12%Bis-Tris gel (catalog number (Cat.No.) NP0322BOX, Invitrogen) with 20 μ l volumes.In MOPS damping fluid (Invitrogen), move, at 180V, carry out 1 hour.Under partial desiccation condition, transfering buffering liquid (NP0006-1, Invitrogen) exist under, at 15V, through 45 minutes, protein transduction is moved on on Nitrocellulose film (Hybond ECL RPN78D, GE Healthcare).Then film is sealed 1 hour in 5% sealing damping fluid (skim-milk, cat170-6404, Biorad) in Tris buffer saline (TBS) 0.1%Tween 20.Then used in sealing damping fluid and be diluted to 1/2000 the primary antibodie (AR441 for androgen receptor, sc-7305, Santa Cruz) exist lower and being diluted to 1/20 in sealing damping fluid, 000 the primary antibodie (Cat.MAB374 for GAPDH, Millipore) under existing, in 4 ℃ of overnight incubation (monitoring Protein Loading).Then film is washed 3 times in lavation buffer solution (TBS, 0.1%Tween 20).Then by film with sealing, be diluted in damping fluid 1/5000, hatch under existing with the anti-mouse immuning ball protein two anti-(goat anti-mouse IgG-HRP, sc 2031, Santa Cruz) of HRP coupling.Then film is washed in lavation buffer solution 3 times.Protein is by electrochemiluminescence (western trace detection system ECL+, Amersham) show, by using photographic film (Biomax light, Sigma) or obtaining system (G:Box, Syngene) by chemoluminescence and detect.
Compound 2 shown in Fig. 2-9,7,10,15,16,19,21,22 effect: these compounds reduce the protein expression of androgen receptors.On the other hand, as shown in figure 10, Nilutamide does not reduce the protein expression (Figure 10) of this receptor.

Claims (25)

1. general formula (I) compound or its pharmaceutically useful salt
Figure FDA0000385311890000011
Wherein:
R 1represent cyano group, nitro, amino ,-NHCOOR 4or-NHCOR 4group;
R 2represent halo, alkyl, haloalkyl or alkoxy base;
R 3represent alkyl group or hydrogen atom; Or two R 3together with the carbon atom that group connects with them, form the cycloalkyl that contains 3-4 member;
X represents
Have the straight or branched alkylidene chain of 3 to 7 carbon atoms, this chain can comprise one or more being selected from-O-,-N (R 5)-other identical or different member;
Or
Figure FDA0000385311890000012
group,
Wherein n1 and p1 are two integers, its n1+p1 and be to be selected from 2,3,4 or 5 integer;
R 6and R 7form together covalent linkage, or R 6and R 7together with the carbon atom connecting with them, form ring or the cycloalkyl that contains 3 to 6 members;
R 4represent alkyl group;
R 5represent hydrogen or alkyl group;
Wherein
Alkyl represents the straight or branched alkyl group that comprises 1 to 12 carbon atom;
Haloalkyl represents alkyl as defined above, and its at least one hydrogen atom is substituted by halogen atom;
Alkoxyl group represents alkyl oxy, and wherein alkyl represents alkyl as defined above.
2. according to the compound or pharmaceutically acceptable salt thereof of claim 1, wherein X represents to have the straight or branched alkylidene chain of 3 to 7 carbon atoms, and described chain can comprise one or more being selected from-O-,-N (R 5)-other identical or different member.
3. according to the compound or pharmaceutically acceptable salt thereof of claim 1, wherein X represents alkylidene chain, and it can comprise single being selected from-O-,-N (R 5)-member.
4. according to the compound or pharmaceutically acceptable salt thereof of claim 1, wherein X represents group, wherein n1 and p1 are two integers, its n1+p1 and be to be selected from 2,3,4 or 5 integer;
R 6and R 7form together covalent linkage, or R 6and R 7together with the carbon atom connecting with them, form
Figure FDA0000385311890000022
ring or the cycloalkyl that contains 3-4 member.
5. according to the compound of claim 4, wherein n1 and p1 equate.
6. according to the compound of claim 1, wherein X represents
Figure FDA0000385311890000023
group, and X ' expression-O-,-N (R 5)-or-(CH 2)-or
Figure FDA0000385311890000024
group, and n2 and p2 be integer, wherein n2+p2's and work as X ' expression-O-or-N (R 5during)-group, be to be selected from 3,4,5,6 and 7 integer, or work as X ' expression or-(CH 2during)-group, be to be selected from 2,3,4 and 5 integer.
7. according to the compound of claim 6, wherein X ' represents
Figure FDA0000385311890000026
group.
8. according to the compound of claim 6, wherein X ' expression-O-,-N (R 5)-Huo – (CH 2)-group.
9. according to the compound of claim 6, wherein n2 and p2 equate.
10. according to the compound of claim 1, wherein R 3represent alkyl group or two R 3together with the carbon atom that group connects with them, form the cycloalkyl that contains 3-4 member.
11. according to the compound of claim 1, wherein R 5represent alkyl group.
12. according to the compound of claim 1, wherein R 1in contraposition.
13. according to the compound of claim 1, wherein R 2in a position.
14. according to the compound of claim 1-, wherein R 6and R 7form together covalent linkage.
15. according to the compound of claim 1, wherein R 6and R 7together with the carbon atom connecting with them, form
Figure FDA0000385311890000031
ring.
16. according to the compound of claim 1, wherein R 6and R 7together with the carbon atom connecting with them, form the cycloalkyl that contains 3 to 6 members.
17. according to the compound of in claim 1-16, and wherein said alkyl group represents methyl group.
18. are selected from following general formula (I) compound:
1,1 '-butane-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
1,1 '-(oxygen base two ethane-2,1-bis-bases) 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione }
4,4 '-[pentane-1,5-bis-bases two (4,4-dimethyl-2,5-dioxo alkyl imidazole-3,1-bis-bases)] two (2-methyl benzonitriles)
1,1 '-(2Z)-but-2-ene-Isosorbide-5-Nitrae-bis-base 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione }
Or its pharmacologically acceptable salt.
19. general formulas (I) compound, be selected from compound 1,1 '-pentane-1,5-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)-phenyl] imidazolidine-2,4-dione } or compound 1,1 '-(2Z)-but-2-ene-1,4-bis-bases 25,5-dimethyl-3-[4-nitro-3-(trifluoromethyl) phenyl] imidazolidine-2,4-dione } or its pharmacologically acceptable salt.
20. methods for the preparation of formula as defined in claim 1 (I) compound, described method comprised by the stage forming below:
(i) by the aryl glycolylurea of the general formula of two equivalents (II)
Figure FDA0000385311890000041
Wherein R 2and R 3as claim 1 defines, and R 1nitro or cyano group,
Under the existence of highly basic with general formula Gp 1-X-Gp 2derivative condensation, Gp 1and Gp 2be leavings group, and X is as defined above,
To form the compound of general formula (I),
Figure FDA0000385311890000042
Wherein R 2, R 3define and R as claim 1 with X 1nitro or cyano group;
Optionally, if R 1be nitryl group, the method also can comprise with the next stage:
(ii) reduction nitryl group is so that acquisition formula (III) compound,
Figure FDA0000385311890000043
Optionally, described method also comprises the following stage that is selected from:
(iii) formula (III) compound and the general formula R that will in the stage (ii), obtain 4the acyl chloride reaction of-COCl, wherein R 4as claim 1 defines, so that acquisition formula (IV) compound,
Figure FDA0000385311890000044
(iv) formula (III) compound and the general formula R that will in the stage (ii), obtain 4the chloro-formic ester reaction of-O-CO-Cl, wherein R 4as claim 1 defines, so that acquisition formula (V) compound,
Figure FDA0000385311890000051
Optionally, if R 6and R 7form together covalent linkage, the method also can comprise with the next stage:
(v) incite somebody to action wherein R 6and R 7form together covalent linkage, thus by R 6and R 7form formula (I) compound oxidation of two keys, so that acquisition formula (VI) compound,
Figure FDA0000385311890000052
21. pharmaceutical compositions, its contain as activeconstituents as defined at least one formula (I) compound and pharmaceutically useful carrier in claim 1 to 19.
22. according in claim 1 to 19 one formula (I) compound for the preparation for the treatment of cancer medicine in purposes.
23. according to the purposes of claim 22, and wherein said medicine is used for the treatment of hormonal dependent cancer.
24. according to the purposes of claim 23, and wherein said medicine is used for the treatment of the cancer of expressing androgen receptor.
25. according to the purposes of in claim 22-24, and wherein said medicine is used for the treatment of mammary cancer or prostate cancer.
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